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New FDA Guidance on Section 522 Postmarket Surveillance Studies

Postmarket Surveillance Under Section 522 of the Federal Food, Drug, and Cosmetic Act.1 This new guidance document provides clarifications regarding the changes to the Food, Drug, and Cosmetic Act (“FDCA” or “the Act”) related to postmarket surveillance studies as implemented by FDA Amendments Act (FDAAA) of 2007 and the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, and replaces the previous guidance on postmarket surveillance issued in 2006 and the draft guidance document issued in 2011.

The new final guidance document provides further clarity on when FDA is authorized to require postmarket surveillance for a medical device per section 522 of the Act, the recommended content of a surveillance plan for submission to FDA and the subsequent interim and final postmarket surveillance reports, as well as the process for FDA’s review of the surveillance plan. The recommendations contained in the final guidance are more detailed than those in the 2011 draft guidance, but the content and procedures are largely unchanged.

Determining When a Postmarket Surveillance Study is Necessary

Section 522 of the Act, 21 U.S.C. § 3601, authorizes FDA to require postmarket surveillance for a class II or class III device at the time of approval or clearance of a device or at any time thereafter, in the following instances:

failure of the device would be reasonably likely to have a serious adverse health consequence;

the device is expected to have significant use in pediatric populations;

the device is intended to be implanted in the body for more than one year; or

the device is intended to be a life-sustaining or life-supporting device used outside of a user facility

Notably, these postmarket surveillance options are distinct from FDA’s ability to request post approval data on PMA devices as a condition of approval. Section 522 of the FDCA allows FDA broader authority to require postmarket surveillance for class II and class III devices and also to require these studies once products have already been on the market. Amendments to Section 522 of the FDCA also permit FDA to request postmarket surveillance data on pediatric devices. Importantly, the ability to require postmarket surveillance for pediatric devices is not strictly limited to devices labeled for use in pediatric population but can be ordered if the device is expected to be used significantly in a pediatric population, regardless of the labeled indications.

In determining whether to require a postmarket surveillance study, FDA may consider premarket data, as well as postmarket data such as adverse event reports, recalls and corrective actions, post-approval data, reports from other governmental authorities, and scientific literature. For example, FDA may order postmarket surveillance to better define the association between problems and devices when unexpected or unexplained serious adverse events occur after a device is marketed. When FDA identifies a potential issue with a device that may warrant postmarket surveillance, the Division of Epidemiology (DEPI) within the Office of Surveillance and Biometrics (OSB) of the Center for Devices and Radiological Health (CDRH) makes a determination regarding whether the statutory requirements for a section 522 order have been met. A cross-Center team including FDA epidemiologists, clinicians, or other experts is then assembled to review the issue(s) in greater depth. FDA may also choose to engage external stakeholders prior to the issuance of a 522 order. In practice, this has meant that FDA can convene an advisory panel meeting to discuss safety issues that have been raised by a device.

Postmarket surveillance studies under section 522 may be ordered at the time of device approval or clearance or any time thereafter by the DEPI. Over the past several years, FDA has been using 522 orders more frequently where a safety signal has been raised in the postmarket setting. For example, since 2011, FDA has issued 522 orders that apply broadly to categories of devices (metal on metal hips, temporomandibular prostheses, vena cava filters, transvaginal mesh, and duodenoscopes).

The duration of follow-up for 522 studies can be up to 36 months unless the manufacturer and FDA agree to an extended timeframe or, if there is no agreement, after the completion of a dispute resolution panel meeting per section 562 of the Act. However, FDA is authorized to require prospective surveillance periods of more than 36 months for devices expected to have significant use in pediatric populations if this extended follow-up period is necessary in order to assess the impact of the device on growth and development, or the effects of growth, development, activity levels, or other factors on the safety or efficacy of the device.

Designing a Postmarket Surveillance Plan

Manufacturers must submit a postmarket surveillance plan to FDA within 30 days of receipt of a 522 order, and must commence surveillance no later than 15 months after the day the order is issued.

The guidance describes the content of the plan to ensure that the proposal submitted meets the requirements of 21 CFR § 822.9 and § 822.10. In general, the plans should be quite similar to a robust clinical study protocol, though they also need to include additional information regarding the timing of the study conduct and completion.

The guidance describes several different types of postmarket surveillance designs that may be used including randomized clinical trials, prospective and retrospective cohort studies, cross-sectional studies, enhanced and active surveillance, meta-analyses, and bench and animal studies. Importantly, the final guidance now includes prospective and retrospective real-world data, such as registries and electronic health records, as a potential source of surveillance data, which was not in the draft guidance. In recent years, FDA has demonstrated its willingness to use registry studies to satisfy some postmarket requirements. The guidance also notes that the agency intends to issue a separate guidance on the use of real-world evidence in postmarket surveillance studies.

Once a postmarket surveillance plan is submitted to FDA, the agency will review the plan within 60 calendar days to determine whether it is administratively complete and if the proposal will result in the collection of useful data to answer the surveillance question(s). If the submission is administratively incomplete (e.g., requirements for study plan, outlined in Appendix 1 of the guidance, are not provided), then the agency will issue a “Not Acceptable” letter. If the agency finds the surveillance plan adequate, then they will issue an approval letter. “Minor Deficiency” and “Major Deficiency” letters may be issued if there are modifications or additional information needed before the plan is approved. Finally, disapproval letters are issued if FDA determines that a new plan is needed to collect useful data to address the postmarket surveillance questions in the 522 order. Companies should plan to interactively work with FDA to finalize the study plan to ensure it is able to initiate data collection within 15 months from the date the 522 order was issued. The guidance states that FDA is willing to interactively discuss surveillance plans throughout the review process, and this is consistent with our recent experience with the agency.

Subsequent to FDA approval of a plan, in the instance that a manufacturer wishes to change the postmarket surveillance plan in a way that may affect the nature or validity of the data collected, the company will need to submit a supplement to FDA for approval, prior to implementation of the change. Supplements are subject to the same review process and the five types of decision letters mentioned above.

Interim and Final Postmarket Surveillance Reports

Unless otherwise specified in the 522 order, manufacturers should submit an interim report every 6 months for the first two years of postmarket surveillance and annually thereafter from the date of the surveillance plan approval or other negotiated start date. Final reports providing the comprehensive data set should be submitted no later than 3 months after study/surveillance completion. The guidance provides a detailed outline for the content and format of interim and final reports. FDA has 60 days to complete the review of any interim reports and 90 days for a final report. FDA’s review of interim and final reports will evaluate the collected data in accordance with the approved plan, with a focus on whether the information in the final report addresses the public health question(s) at issue in the 522 order. OSB may consult with various centers and offices within FDA to ensure the data are assessed appropriately. As needed, FDA may request additional information on a report from the manufacturer through an interactive review process and/or through a deficiency letter. If a report includes insufficient data or data that raises new safety and/or efficacy concerns about the device, the agency may request labeling changes, issue safety communications, or take compliance and/or enforcement action. In addition, the guidance also notes that, after reviewing data in a final report, the agency may also issue a new postmarket surveillance order to address new concerns in the data.

Publicly Available Information about Surveillance Plans

FDA maintains a website providing a database of general information about postmarket surveillance studies, including the status of the plans and reports.2

The database provides general information about approved surveillance studies including administrative information (manufacturer, device, and key dates), general surveillance plan parameters (study design and analysis type, data source, comparison group, and patient population), and where applicable, more detailed surveillance plan parameters (sample size, assessments, length of follow-up, etc.). Furthermore, a new addition to the final guidance is the provision that the agency may also post interim summary data on its website if such results raise safety concerns or may otherwise impact treatment. A list of information that FDA can publicly disclose from interim and final reports, which now includes final safety and effectiveness findings and study/surveillance strengths and weaknesses, is included in the guidance.

The agency also posts the status of plans and interim and final reports on the website, according to the date of the 522 order, dates of submission and the dates agreed upon in the surveillance plan. For study/surveillance plans, the agency uses the several categories to define the status of a plan, including “Plan Pending”, “Plan Overdue”, “Study Pending”, or “Study Progress Inadequate” among others. The final guidance also includes three new categories for study status as follows, “Noncompliant” (when it has been more than 15 months since the 522 order date and the study has not started), “Revised/Replaced” (when the manufacturer has not fulfilled or cannot fulfill a 522 order and a new plan has replaced the original plan), and “Consolidated” (when multiple 522 orders for a device or device type have been consolidated into one 522 order). For interim and final reports, the agency uses the following categories: “Report On Time”, “Report Overdue”, or “Report Overdue/Received.”

FDA Enforcement Action and Appeal Pathways

The guidance notes that failure to comply with a 522 order may lead to FDA taking enforcement action. Accordingly, in addition to the company’s compliance status being posted on FDA’s website, FDA may choose to use one of its additional enforcement tools, such as issuance of an United Letter or Warning Letter, if a company fails to submit a plan or update the agency on the plan’s progress.

Accordingly, in instances where a company believes it may be impossible to complete a postmarket surveillance order, or if a manufacturer disagrees with the agency about the content of a plan or a disapproval decision, the manufacturer should expeditiously request an exemption from the order, and proceed through the applicable appeals pathway as needed. Specifically, the manufacturer may request a meeting with the Office Director of OSB, seek internal review of FDA’s decision through the appeal process under 21 CFR § 10.75, request an informal regulatory hearing under 21 CFR § Part 16, or request review by the Medical Devices Dispute Resolution Panel of the Medical Devices Advisory Committee. That being said, in our experience, it is often difficult to convince FDA that a postmarket surveillance study cannot be completed. Notably, even in instances where a manufacturer has stopped marketing the device subject to a postmarket surveillance order, it may still need to conduct postmarket surveillance unless specifically exempted by the Agency.

In summary, the new final guidance provides a comprehensive resource for companies subject to 522 orders.

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